KRAB-zinc finger proteins evolve to control mobile DNA elements and facilitate their adaptation as novel regulators of gene expression

Authors

• G Wolf
• M Tinkham
• D Hoang
• A Mitra
• A De Iaco
• M Sun
• T Macfarlan

Abstract

Mammalian genomes encode several hundred Krüppel-associated box zinc finger proteins (KRAB-ZFPs) that bind DNA in a sequence-specific manner through tandem arrays of C2H2-type zinc fingers and induce epigenetic silencing via its cofactor KAP1. Recent evidence suggests that KRAB-ZFPs evolved to control transposable elements (TEs) that continuously arise and amplify within host genomes. However, the vast majority of KRAB-ZFPs have not been investigated to date and their function and biological significance remain unknown. To shed light on KRAB-ZFP function in the mouse, we first determined the genomic binding sites of 19 previously uncharacterized murine KRAB-ZFPs and show that the majority of these transcription factors indeed target various groups of TEs, including highly active LTR retrotransposons such as IAP and ETn elements. To test whether KRAB-ZFPs are functionally required to repress TEs, we used CRISPR/Cas9 technology to genetically delete five of the largest KRAB-ZFP gene clusters encoding more than 100 of the approximately 360 mouse KRAB-ZFPs in embryonic stem cells (ESCs). Genome-wide RNA expression analysis revealed strongly increased TE expression in two of the KRAB-ZFP cluster knockout ESC lines, accompanied by H3K9me3 and DNA methylation loss as well as an increase in histone marks associated with transcription and active enhancers. Finally, we show that enhancer elements within ETn retrotransposons have a strong effect on the expression of nearby genes in the absence of ETn-targeting KRAB-ZFPs. In conclusion, our data supports a model in which KRAB-ZFPs primarily evolve to repress potentially hazardous retrotransposons and, in some cases, also control novel TE-borne enhancer elements, allowing the establishment of species-specific gene regulatory patterns.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Friday, March 26, 2021